In the disease known as diabetes mellitus, the pancreas loses its ability to manufacture and secrete insulin to counter rising blood glucose concentrations, and metabolic imbalance results. Historically, the disease has been treated by insulin injection, diet, exercise and, in limited cases, oral medication. However, the treatment has been only marginally successful at best.
A proposed solution is the artificial pancreas, a bedside device having intravenous catheters for blood glucose sampling and insulin infusion, a glucose analyzer and an insulin pump controlled by algorithms that take into account information from the glucose analyzer. But there is a clear need to develop a convenient miniature version that could be implanted to provide the patient with totally automatic metabolic regulation. A suitable insulin pump component for implantation on a clinical scale has already been developed. But the glucose sensing component remains a problem.
An electrolytic glucose sensor capable of assaying glucose in complex fluids such as blood that has been removed from the body and exposed to the atmosphere is disclosed in U.S. Pat. No. 3,542,662 to Hicks et al, dated Nov. 24, 1970. In this sensor, an enzyme-containing membrane is disposed between a fluid being assayed and a first oxygen sensor electrode and a similar membrane not containing enzyme is disposed between the fluid and a second reference oxygen sensor electrode.
In this sensor, a certain portion of the oxygen diffusing through the enzyme-containing membrane is consumed by equimolar reaction with glucose catalyzed by the enzyme and is therefore unavailable for detection by the first oxygen sensor electrode. The second, reference oxygen sensor electrode in which the membrane does not include enzyme, determines the concentration of oxygen that would have been detected had not the enzyme-promoted reaction occurred. And the difference in oxygen detected by the two electrodes is relied on as proportional to the glucose concentration.
However, when efforts were made to adapt this device for use directly in the body, confusing observations resulted. The sensors were calibrated for glucose response in the atmosphere before implantation in test animals. After a period of implantation, glucose or insulin was injected intravenously to perturb the blood glucose concentration. In the cases where there was any response to glucose, the sensor-indicated concentration was much less than expected.
The departure from expected behavior has been attributed universally to unfavorable biocompatibility of the implant material. That is, implants cause the development of an encapsulating sheath which, if thick and dense, may be impermeable to glucose. However, this can be minimized by the use of appropriate materials and does not adequately account for the results secured.
A key problem is that the glucose concentration in the body is normally higher than the oxygen concentration by a factor of 50 to 100 times. Since the enzyme reaction is limited by the least abundant reactant, an implanted sensor would respond to oxygen concentration rather than to glucose concentration and therefor would be ineffective to measure glucose concentration.
One proposal to solve this problem presented in an article by Fischer and Abel entitled "A Membrane Combination for Implantable Glucose Sensors, Measurements in Undiluted Biological Fluids" in Trans. Am. Soc. Artif. Intern. Organs, Vol. XXVIII, 1982, involved sandwich membranes for association with an oxygen electrode sensor. In these membranes, a hydrophobic layer was disposed to cover an enzyme layer and a minute hole directly aligned with the anode of the sensor was provided in the hydrophobic layer to allow access of glucose from blood being assayed without dilution to the enzyme and anode. Oxygen diffusing through the surface of the entire hydrophobic layer was indicated to provide a stoichiometric excess over the glucose.
The space and time within which reaction between glucose and oxygen must occur in this arrangement are so limited as to impose limits on the range of concentrations of glucose with which complete reaction can occur and could affect the reliability of results obtained. Additionally, the small amount of enzyme disposed for action on glucose entering the minute hole tends to become inactivated in a relatively short time.